Process for preparing c-acetylated and o-acetylated compounds



Patented June 7, 1949 PROCESS FOR PREPARING C-ACETYLATED ANDO-ACETYLATED COMPOUNDS John A. Spence, San Pablo, Calif., and Edward F.Degering, West Lafayette, Ind., assignors to Purdue Research Foundation,La Fayette, Ind., a corporation of Indiana N Drawing. ApplicationDecember 5, 1946, Serial No. 714,144

13 Claims. 1

This invention relates to a process for preparing C-acetylated andO-acetylated compounds.

In our copending application Serial No. 556,887, filed October 2, 1944(now United States Patent 2,407,302, dated September 10, 1946), we haveshown that p-ketocarboxylic esters and ketenes react, in the presence ofcertain acid catalysts, e. g. sulfuric acid, chlorosulfonic acid,sulfamic acid, etc., to give enol esters. On the other hand, we havefound, as shown in our copending application Serial No. 613,698, filedAugust 30, 1945 (now United StatesPatent 2,417,381, dated March 11,1947), that ketene and fl-ketocarboxylic esters react to giveC-acetylated compounds when no catalyst is present.

We have now found that S-ketocarboxylic esters and ketene react, in thepresence of tertiary amines, to give both C-acetylated and O-acetylatedcompounds.

It is, accordingly, an object of our invention to provide a new processfor preparing C-acetylated and O-acetylated compounds. Further objectswill become apparent hereinafter.

In accordance with our invention, we react ketene with aB-ketocarboxylic ester selected from those represented by the followinggeneral formula:

n- 'icrn '3'-om wherein R and R1 each represents a hydrocarbon radical,e. g. a member selected from the group consisting of alkyl groups,aralkyl groups and aryl groups, in the presence of a tertiary aminecatalyst.

Usually in our new process, two simultaneous reactions take place withthe -formation of C-acetylated compounds which can be represented by thefollowing general formula:

n-c-oH-c-om wherein R and R1 have thevalues given above, andO-acetylated compounds which can be represented by the following generalformula:

III. 000cm wherein R and Ri have the values given above. TheC-acetylated and O-acetylated compounds can be separated as shownhereinafter. Depending upon the starting B-ketocarboxylic ester and uponthe particular tertiary amine employed as catalyst, we have found thatthe proportion of C-acetylated to o-acetylated compound varies,Moreover, in our process, We frequently obtain substantial amounts ofenol acetate which can be represented by the following general formula:

wherein R. and R1 have the values given above. These latter enolacetates are formed apparently by the action of ketene upon theC-acetylated compounds represented by Formula II above.

Typical examples of the starting B-ketocarboxylic esters (Formula Iabove) include methyl acetoacetate, ethyl acetoacetate, benzylacetoacetate, phenyl acetoacetate, ethyl propionoacetate, methyln-butyroacetate, ethyl benzoylacetate, ethyl de'canoylacetate, etc.

Typical examples of the tertiary amine-catalysts include triethylamine,tri-n-butylamine, triamylamines, diethyl-n-butylamine, tribenzylamine,dimethylam'line, diethylaniline, pyridine, N-methylpiperidine,'dimethyl-n-propylamine, trimethylamine, triisobutylamine,triisopropylamine, etc.

In practicing our invention, the ,B-ketocarboxylic ester and tertiaryamine catalyst are placed in a reaction vessel. The contents of thereaction vessel are then raised to reaction temperature and ketene(CI-I2=C=O), preferably freshly prepared, is added to the contents ofthe reaction vessel at a rate which substantially precludes the buildingup in the reaction mixture of any substantial quantity of unreactedketene. The dispersion of the ketene in the reaction mixture isadvantageously facilitated by agitation of the reaction mixture.Agitation also aids in avoiding local overheating of the reactionmixture. The addition of ketene is advantageously continued until aquantity has been added which is at least 0111' invention.

The process of our invention takes place over a wide temperature range.Usually we have found that the reaction takes place at an appreciablerate at from about 60 C. to about 130 (3., although higher or lowertemperatures can be employed. Especially with the higher molecularweight B-ketocarboxylic esters, higher temperatures should be avoided inorder to avoid thermal decomposition of the compounds. The heat ofreaction may require cooling of thereaction mixture to control thetemperature within the desired range. v I a If desired a reaction mediumwhich is inert to the ketene and the ,B-ketocarboxylic ester, e. g. asaturated aliphatic hydrocarbon or an aromatic hydrocarbon can beemployed. However, a reaction medium is unnecessary in the case of most,B-ketocarboxylic esters which are liquid at the reaction temperatureemployed.

As pointed out above C-acetylated and O-acetylated compounds areproducedsimultaneously in our new process. The mixture of. C -acetylated andO-acetylated compounds is advantageously distilled from thereactionmixture and the O- acetylated compound separated from themixture by treating the mixturewith an aqueous solution of an alkalimetal carbonate, e. g. sodium carbonate. The C-acetylated compounddissolves in the aqueous alkali metal carbonate solution, leaving thewater-insoluble O-acetylated compound. The C-acetylated compound and O-acetylated compound can also be separated by treating the mixturewithanaqueous solution of a water-soluble copper salt, e. g. cupric acetate.The copper salt of the Ceacetylated compound precipitates, leaving thewater-insoluble O-acetylated compound. The coppersaltof the C-acetylatedcompound can then be hydrolyzed, in the presence oi an acid, e. sulfuricacid, to regenerate the C,- acetyl ated compound.

The following examples will serve to illustrate further the manner ofpracticing our invention:

EXAMPLE 1.KETENE AND ETHYL AcsroAcE'rA'rE, PRESENCE OF A TERTIARY AMINE65 g. (0.5 mole) of ethyl ,acetoacetate and 0.007 mole of tertiary aminewere placed in a reaction vessel. From 1.2 to 1.4 moles of .ketene(CH2=C=O), generated by the pyrolysis of acetone, was passed into themixture of ethyl acetoacetate and tertiary amine over a period of twohours, while maintaining a reaction temperature of 105:5 C. andvigorously agitating-the mixture. The reaction mixture was thendistilled under reduced pressure and thereaction product boiling at85-100 C. at mm. of Hg pressure was rectified using a small Podbielniakcolumn. The fraction boiling at 87- 89 C. at 10 mm. of Hg pressure was amixture of the enol acetate having the formula:

oooon o oHr-t=oH-o -oo,m and ethyl diacetylacetate having the formula:

CHJC O El) CH-C-OCiHs When tributylamine, diethylaniline or pyridine wasused as the tertiaryamine catalyst, the enol acetate of ethyldiacetylacetate was also isolated from the reaction mixture as anoilboiling at 130-133 C. at 10 mm. of Hg pressure.

Table I m)" of mixture Enol acetate mm. mixture ethyl (n- Teriiary amineacctyl acetate 17 ml. 20 In]. 40 ml.

I Reaction temperature of (SO- 0. used.

EXAMPLE 2.-SEPARATION or MIXTURE or ENoL ACETATE or ETHYL ACETOACETATEAND ETHYL DIAc'ErYLAcETArE-SonIUM CARBONATE SOLUTION METHOD v 21 g. ofthe mixture, obtained when tri-nbutylamine was employed as catalyst andhaving an index of refraction (11 between 1.4485 and 1.4428, was shakenwith two 10 m1. portions of aqueous sodium carbonate solution (10 percent by..weight). The water insoluble oil was then dried over anhydrouscalcium chloride. The dried oil had an index-of refraction, (n of 1.4406which agreeswith thatbf the enol acetate of ethyl acetoacetate, 18.5 g.of the. enol acetate of ethyl acetoacetate was thus obtained. In thiscase; pure ethyl .diacetylacetate wasnot isolated, but its presence wasestal alished when its copper salt (melting at 152 C.) was isolated.This sodium carbonate solution. method ,of separation of. isomers issatisfactory forisolation of the enol acetate of ethylacetoacetatewhenflthe enol acetate is the predominant part of the mixture.

EXAMPLE 3. -SEPARAr oN or Mrxrmis or .ENoL

ACETATE or ETHYL AosroAcsrArn Np ETHYL DI- ACETYL ACETATE-COPPER SALTMETHOD 48 g. of the mixture (87-90? C./10 mm.; 11 214635) obtained whentribenzylamine was employed as a catalyst and 400 ml. of a saturatedaqueous copper acetate solution were shaken together intermittently overa period of one hour. The blue precipitate which formed was removed byfiltration and washed with four 40 ml. portions of water; The air-driedblue salt. was then washed with two 50;ml. portion s of cold diethylether. 3 The blue salt (55.2 g.) was recrystallized from 60 ml. ofabsolute ethanol. 48 g. (M. P. 148-150 C.) was obtained. This quantityof salt is equivalent to 40.8 g of ethyl diacetyl acetate. The blue saltcan be hydrolyzed with dilute sulfuric acid to yield ethyl diacetylacetate.

The following tablesummarizesthe separation of the mixture given in theabove Table I.

1 Obtained from 26 g. er the mixture (av-90 ol m mm).

The enol acetate of ethyl diacetylacetate (BO-133 C./ mm.) does not forma copper salt. Its 2,4-dinitrophenylhydrazine derivative melts at 157 to159 C. This same enol acetate was prepared by reaction of ketene withethyl diacetylacetate in the presence of sulfuric acid, as shown in thefollowing example.

EXAMPLE 4.ENOL ACETATE or ETHYL DIACETYLACETATE 0.3 mole (51.6 g.) ofethyl diacetylacetate and 0.004 mole of concentrated sulfuric acid wereplaced in a reaction vessel. Approximately one mole of ketene (CH2=C'=O)was passed into the ethyl diacetylacetate during a period of 1.4 hours,while maintaining a reaction temperature of 105:15" C. and vigorouslyagitating the contents of the reaction vessel. The resulting reactionmixture was then allowed to stand for hours at a temperature between andC. and then the mixture was distilled under reduced pressure. 46 g. ('72per cent yield) of the enol acetate, boiling at 116'-118 C. at 5 mm. ofHg pressure, was obtained.

EXAMPLE 5.KETENE AND ETHYL BENZOYLACETATE, PRESENCE or TRI-N-BUTYLAMINE20 g. (0.104 mole) of ethyl benzoylacetate and 0.3 g. (0.0016 mole) oftri-n-butylamine were placed in a reaction vessel. 5.5 g. (0.13 mole) ofketene (CH2=C=O) generated by the pyrolysis of acetone, were passed intothe mixture of ethyl benzoylacetate and tri-n-butylamine, over a periodof about one hour, while keeping the temperature of the mixture between67 and 75 C. The reaction mixture, after the addition of ketene, wasreddish-brown, but had very little color. It was dissolved in 25 ml. ofdiethyl ether and the ether solution treated to separate theC-acetylated and O-acetylated derivatives, according to the method ofBernhard, Ann. 282, 153 (1894) as follows: the ether solution was shakenwith two 20-ml. portions of aqueous potassium carbonate solution (10 percent by weight) to extract the C-acetylated compound, i. e. ethylbenzoylacetylacetate. Then, the ether solution was shaken with two20-ml. portions of aqueous potassium hydroxide (10 per cent by weight)to extract the unreacted ethyl benzoyl acetate. The residual ethersolution contained the O-acetylated compounds. The potassium carbonatesolution and the potassium hydroxide solution were then each acidifiedwith sulfuric acid and the oil which separated in each case was taken upin separate portions of diethyl ether. These two ether extracts and theether solution remaining from the alkaline extractions were each driedover anhydrous sodium sulfate. The ether was removed from each of thethree dried extracts by heating on a steam bath, passing dehydrite driedair into each extract to speed up the removal of the ether. From theether extracts the following were obtained:

28 I. (Potassium carbonate soluble), 1.0 g. 1.5390 II. (Potassiumhydroxide soluble),8.8 g. 1.5310 III. (Alkali insoluble), 9.0 g 1.5202

Product I reacted with aqueous cupric acetate to give a precipitate of asky blue salt, which after recrystallization from benzene melted at 223to P of ethyl benzoylacetylacetate and unreacted ethyl benzoylacetate.Product III was the enol acetate of ethyl acetylbenzoylacetate. Itreacted exothermically with phenylhydrazine to give acetylphenylhydrazine (CeHsNH-NHCOCHs) and 4-carbethoxy-Zi-methyl-1,5-diphenylpyraz0le, melting at 128.5 to 129 C.and 119 to 120 0., respectively.

In the manner illustrated in the foregoing examples methyl acetoacetate,benzyl acetoacetate, phenyl'acetoacetate, ethyl propionoacetate, ethyldecanoylacetate, etc., can be acetylated with ketene, in the presence ofa tertiary amine.

What we claim as our invention and desire to be secured by LettersPatent of the United States is:

1. A process for preparing an O-acetylated compound and a C-acetylatedcompound comprising reacting ketene with a ketoester selected from thoserepresented by the following general formula:

0 0 ll H RCCH2COR1 wherein R and R1 each represents a hydrocarbonradical, in the presence of at least one basic tertiary amine catalyst,and separating the O-acetylated and C-acetylated compounds.

2. A process for preparing a mixture of an O-acetylated and C-acetylatedcompound com prising reacting ketene with ethyl acetoacetate, in thepresence of at least one basic tertiary amine catalyst. 3. A process forpreparing an O-acetylated compound and a C-acetylated compoundcomprising reacting ketene with ethyl acetoacetate, in the presence ofat least one basic tertiary amine catalyst, and separating theO-acetylated and C-acetylated compound.

4. A process for preparing a mixture of O-acetylated and C-acetylatedcompounds comprising reacting ketene with ethyl acetoacetate in thepresence of at least one trialkylamine wherein each alkyl group is ofthe formula C11H21L+l wherein n represents a positive integer of from 1to 5.

5. A process for preparing a mixture of O-acetylated and C-acetylatedcompounds comprising reacting ketene with ethyl acetoacetate, in thepresence of at least one trialkylamine wherein each. alkyl group is ofthe formula CnH2n+l wherein n represents a positive integer of from 1 to5, and separating the O-acetylated and C-acetylated compounds.

6. A process for preparing a mixture of O-acetylated and C-acetylatedcompounds comprising reacting ketene with ethyl acetoacetate, in thepresence of tri-n-butylamine.

'7. A process for preparing a mixture of O-acetylated and C-acetylatedcompounds comprising reacting ketene with ethyl acetoacetate, in thepresence of tri-n-butylamine, and separating the C-acetylated andO-az'cetylated compounds.

8. A process for preparing a mixture of O-acetylated and C-acetylatedcompounds comprising reacting ketene with ethyl benzoylacetate, in thepresence of at least one basic tertiary amine.

9. A process for preparing a mixture 01' O-acetylated and C-acetylatedcompounds comprising reacting ketene with ethyl benzoylacetate, in thepresence of at least one basic tertiary amine, and separating theO-acetylated and C-acetylated compounds.

10. Al process for preparing a. mixture of 7 O-acetylate'd andC-acetylated compounds comprising reacting ketene with ethylbenzoylacetate, in the presence of at least one trialkylamine whereineach alkyl group is of the formular C1LH2n+1 wherein n represents apositive integer of from I to 5.

11'. A process for preparing a mixture of O-acetylated and C-acetylatedcompounds comprising reacting ketene with ethyl benzoylacetate, in thepresence of at least one trialkylamine wherein each alkyl group is ofthe formula CnHS'n-l-I wherein n represents a positive integer of from 1to 5, and separating the O-acetylated and C-acetylated compounds.

. 1-2. A process for preparing a, mixture of O-acetylated andC-acetylated compounds comprising reacting ketene with ethylbenzoylacetate, in the presence of tri-n-butylamine.

13. A process for preparing a mixture of REFERENCES CITED The followingreferences are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,351,366 Pohl et al'. June 13,1944 2,407,301 Spence et a1. Sept. 10, 1946 2,407,302 Spence et al Sept.10, 1946 2,417,381 Spence Mar. 11, 1947

